The present invention is in the field of medicine, particularly in the treatment, of Type II diabetes and obesity. More specifically, the present invention relates to selective xcex23 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.
The current preferred treatment for Type II, non-insulin dependent, diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. There are no currently approved medications that adequately treat either Type II diabetes or obesity. The invention described herein is directed toward an effective and timely treatment for these serious diseases.
One recently recognized therapeutic opportunity involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as xcex23 adrenergic receptor agonists have been shown to exhibit a marked effect on Lipolysis, thermogenesis, and serum glucose levels in animal models of Type II diabetes.
The xcex23 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the xcex21 and xcex22 receptor subtypes yet is considerably less abundant. The importance of the xcex23 receptor is a relatively recent discovery since the amino-acid sequence of the human receptor was only elucidated in the late 1980""s. A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the xcex23 receptor. Despite these recent developments there remains a need to develop a selective xcex23 receptor agonist which has both high intrinsic activity and minimal agonist activity against the xcex21 and xcex22 receptors.
The present invention provides a novel compound represented by Formula (I) below and methods of treating Type II diabetes, treating obesity, and stimulating the [3 receptor which comprise administering to a patient in need thereof a compound described by Formula I below. 
wherein:
X1 is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, or a bond;
R1 is a heterocycle of the formula: 
R2 and R3 are independently hydrogen, C1-C4 alkyl, or aryl;
R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of: 
X2 is a bond, or a 1 to 5 carbon straight or branched alkylene;
R5 is hydrogen or C1-C4 alkyl;
R6 is hydrogen or C1-C4 alkyl;
or R5 and R6 combine with the carbon to which each is attached to form a C3-C6 cycloalkyl;
or R6 combines with X2 and the carbon to which each is attached to form a (C3-C8 cycloalkyl;
or R6 combines with X2, R4, and the carbon to which each is attached to form: 
provided that R5 is hydrogen;
R7 is hydrogen, hydroxy, cyano, oxo, COnR2, CONHR2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 optionally substituted alkyl, (CH2)n aryl, (CH2)nheterocycle, (CH2)n optionally substituted aryl, or (CH2)n optionally substituted heterocycle;
R8 is independentLy hydrogen, halo, or C1-C4 alkyl;
R9 is halo, CN, OR10, C1-C4 alkyl, C1-C4 haloalkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), SR2, CSNHR2, CSNR11R12, SO2R2, SOR2, NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2, or CONR11R12;
R10 is C1-C4 alky:, C1-C4 haloalkyl, (CH2)nC3-C8 cycloalkyl, (CH2)naryl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, or (CH2)n optionally substituted heterocycle;
R11 and R12 are independently hydrogen, C1-C4 alkyl, aryl, (CH2)naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperaziny_;
R13 is hydrogen, halo, aryl, or C1-C4 alkyl;
m is 0 or 1;
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also provides novel pharmaceutical formulations of the compounds of Formula I.
The present invention also provides a novel compound of Formula (I) wherein all variables except R4, R6 and R9 are as described above. R4 additionally includes thiophene optionally substituted with R9; R9 additionally includes NR2SO2R2 and SO2NR11R12; and R6 is: 1) hydrogen or C1-C4 alkyl; 2) R5 and R6 combine with the carbon to which each is attached to form a C3-C6 cycloalkyl; 3) R6 combines with X2 and the carbon to which each is attached to form a Z or Zxe2x80x94CH2, wherein Z is a C3-C8 cycloalkyl attached to the nitrogen atom in Formula (I); or 4) R6 combines with X2, R4, and the carbon to which each is attached to form: 
provided that R5 is hydroger.
Also included are methods of stimulating beta 3 receptors in a mammal in need thereof and methods of treating a mammal with Type II diabetes or obesity using a compound represented by Formula (I), modified as described in the previous paragraph. The method comprises administering a pharmaceutically effective amount of said compound.
The compounds of Formula I are selective xcex23 receptor agonists and as such are useful for treating Type II diabetes and obesity, as well as useful for stimulating the xcex23 receptor. Therefore, the present invention also provides for methods of treating Type II diabetes and obesity, as well as a method of stimulating the xcex23 receptor.
For the purposes of the present invention, as disclosed and claimed herein, the following terms, as used herein, are defined below. As they relate to the present invention, the terms below may not be interpreted, individually or collectively, to describe chemical structures that are unstable or impossible to construct.
The term xe2x80x9chaloxe2x80x9d represents fluorine, chlorine, bromine, or iodine.
The term xe2x80x9cC1-C4 alkylxe2x80x9d represents a cyclo, straight, or branched chain alkyl group having from one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and the like. A xe2x80x9chaloalkylxe2x80x9d is one such alkyl substituted with one or more halo atoms, preferably one to three halo atoms. An example of a haloalkyl is trifluoromethyl. An xe2x80x9calkoxyxe2x80x9d is a alkyl group covalently bonded by an xe2x80x94Oxe2x80x94 linkage.
The term xe2x80x9c1 to 5 carbon straight or branched alkylenexe2x80x9d represents a one to five carbon, straight or branched, alkylene moiety. A branched alkylene may have one or more points of branching. A 1 to 5 carbon straight or branched alkylene may optionally be unsaturated at one or more carbons. Thus, a 1 to 5 carbon straight or branched alkylene includes 1 to 5 carson alkylene, alkenylene and alkylidene moieties. Examples include but are not intended to be limited to methylene, ethylene, propylene, butylene, xe2x80x94CH(CH3)CH2xe2x80x94CH(C2H5)CH2xe2x80x94, xe2x80x94CH(CH3)CH(CH3xe2x80x94CH2C(CH3)2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CHxe2x95x90, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2xe2x80x94Cxe2x95x90CCH2xe2x80x94, and the like.
The xe2x80x9cacylxe2x80x9d moiety, alone or in combination, is derived from an alkanoic acid containing from one to seven carbon atoms. The term xe2x80x9cacylxe2x80x9d also includes moieties derived from an aryl carboxylic acid.
The term xe2x80x9carylxe2x80x9d represents an optionally substituted or unsubstituted phenyl or naphthyl. The term (CH2)naryl is preferably benzyl or phenyl.
The term xe2x80x9coptionally substitutedxe2x80x9d as used herein means an optional substitution of one to three, preferably one or two groups independently selected from halo, C1-C4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R12, CONH(C1-C4 alkoxy), cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, benzyl, nitro, NR11R12, NHCO(C1-C4 alkyl), NHCO(benzyl), NHCO(phenyl), SR2, S(C1-C4 alkyl), OCO(C1-C4 alkyl), SO2(C1-C4 alkyl), or SO2(phenyl); provided that such substitution does not entirely destroy biological activity, as defined in this specification.
R2 and R3 are independently hydrogen, C1-C4 alkyl, or aryl.
R11 and R12 are independently hydrogen, C1-C4 alkyl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl.
The term xe2x80x9cheterocyclexe2x80x9d represents a stable, optionally substituted or unsubstituted, saturated or unsaturated 5 or 6 membered ring, said ring having from one to four heteroatoms that are the same or different and that are selected from the group consisting of sulfur, oxygen, and nitrogen. When the heterocycle contains two adjacent carbon atoms, the adjacent carbon atoms may be structured to form a group of the formula xe2x80x94CHxe2x95x90CHxe2x80x94; provided that (1) when the heterocyclic ring contains 5 members, the heteroatoms comprise not more than two sulfur or two oxygen atoms but not both, and (2) when the heterocyclic ring contains 6 members and is aromatic; sulfur and oxygen are not present. The heterocycle may be attached at any carbon or nitrogen which affords a stable structure. Examples of heterocycles include, but are not intended to be limited to, pyrazole, pyrazoline, imidazole, isoxazole, triazole, tetrazole, oxazole, 1,3-dioxolone, thiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, piperazine, morpholine, pyrazine, pyrrolidine, piperidine, oxazolidone, oxazolidinedione, imidazolidinone, and the like.
The term xe2x80x9cleaving groupxe2x80x9d as used in the specification is understood by those skilled in the art. Generally, a leaving group is any group or atom that enhances the electrophilicity of the atom to which it is attached for displacement. Preferred leaving groups include but are not intended to be limited to p-nitrobenzene sulfonate, triflate, mesylate, tosylate, imidate, chloride, bromide, iodide, and the like.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d, as used herein, represents an amount of a compound of the invention that is capable of stimulating the xcex23 receptor in mammals. The particular dose of the compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the patient, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
The term xe2x80x9ctreating,xe2x80x9d as used herein, describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, to alleviate the symptoms or complications, or to eliminate the disease, condition, or disorder.
The term xe2x80x9cselectivexe2x80x9d means preferential agonism of the xcex23 receptor over agonism of the xcex21 or xcex22 receptor. In general, the compounds demonstrate at least about a twenty fold differential (preferably over a 50 fold differential) in the dosage required to behave as an agonist to the xcex23 receptor and the dosage required for equal agonism of the xcex21 and xcex22 receptors as measured in the Functional Agonist Assay as described hereinafter. The compounds demonstrate this differential across the range of doses. Thus, xcex33 selective compounds behave as agonists for the xcex23 receptor at much lower concentrations with lower toxicity by virtue of their minimal agonism of the other receptors.
As previously noted, the present invention provides a method of treating type II diabetes and obesity, comprising administering to a mammal in need thereof compounds of the Formula I.
Referring again to Formula I, preferred embodiments of the present invention are set out in the lettered paragraphs below.
(a) R7 is hydrogen.
(b) R7 is C1-C4 alkyl or C1-C4 alkoxy.
(c) R7 is hydroxy, cyano, oxide, COnR2, CONHR2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 optionally substituted alkyl, (CH2)n aryl, (CH2)nheterocycle.
(d) R7 is COnR2 or CONHR2.
(e) R7 is (CH2)n aryl or (CH2)nheterocycle.
(f) R7 is hydroxy or oxo.
(f1) R1 is 
(g) X1 is xe2x80x94OCH2xe2x80x94, the oxygen of which is attached to R1.
(h) X1 is a bond.
(i) R3 is methyl.
(j) R3 is hydrogen.
(k) R5 is methyl or ethyl.
(l) R6 is methyl or ethyl.
(m) R5 and R6 are both methyl.
(m) R5 and R6 are both hydrogen.
(n) X2 is isopropylene, methylene, or ethylene.
(n) X2 is isopropylene
(o) X2 is methylene.
(p) X2 is ethylene.
(q) R4 is 
(u) R8 is halo.
(v) R8 is hydrogen.
(w) R9 is halo, CN, OR10, C1-C4 alkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), NR2SO2R2, SO2R2, SO2NR11R12, SOR2, optionally substituted aryl., optionally substituted heterocycle.
(x) R9 is CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), NR2SO2R2, SO2R2, SO2NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12.
(y) R9 is halo, CN, C1-C4 haloalkyl, , SR2, CSNR2, CSNR11R12, SO2R2, SO2NR11R12, SOR2, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12.
(z) R9 is OR10, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12.
(aa) R9 is NR2SO2R2.
(bb) R9 is CN.
(cc) R9 is CONR11R12.
(dd) R9 is OR10.
(ee) R10 is (CH2)nC3-C8 cycloalkyl, (CH2)naryl, (CH2)nheterocycle, said aryl, C3-C8 cycloalkyl, or heterocycle being optionally substituted.
(ff) R10 is (CH2)nC3-C8 cycloalkyl, (CH2)nheterocycle, said C3-C8 cycloalkyl, or heterocycle being optionally substituted.
(gg) R10 is (CH2)nheterocycle said heterocycle being unsubstituted or optionally substituted.
(hh) R10 is aryl.
(ii) R10 is pyridyl.
(jj) R10 is aryl substituted with CONR11R12, CN, CO2R2, or NR2SO2R2.
(kk) R10 is pyridyl substituted with CONR11R12, CN, CO2R2, or NR2SO2R2.
(ll) R10 is aryl substituted with CONR11R2.
(mm) R10 is aryl substituted with CN.
(nn) R10 is aryl substituted with CO2R2.
(oo) R10 is aryl substituted with NR2SO2R2.
(pp) R10 is pyridyl substituted with CONR11R12.
(qq) R10 is pyridyl substituted with CN.
(rr) R10 is pyridyl substituted with CO2R2.
(ss) R10 is pyridyl substituted with NR2SO2R2.
(tt) R13 is hydrogen.
(uu) R13 is halo.
(vv) R13 is (CH2)naryl or (CH2)nheterocycle.
(ww) R13 is (CH2)naryl, (CH2)nheterocycle, or halo.
(xx) R13 is (CH2)naryl or (CH2)nheterocycle, wherein n is 0.
(yy) Preferred optional substitution is halo, C1-C4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R2, cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, benzyl, nitro, NR11R12, NHCO(benzyl), SO2(C1-C4 alkyl), or SO2(phenyl).
(zz) Other preferred optional substitution is halo, C1-C4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R12, cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, nitro, or NR11R12.
(aaa) Other preferred optional substitution is halo, hydroxy, carboxy, acyl, COOR2, CONR11R12, cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, or NR11R2.
(bbb) Other preferred optional substitution is halo, hydroxy, acyl, C1-C4 alkoxy, C1-C4 alkyl, or phenyl.
(ccc) Preferred halo groups include bromine, chlorine, or fluorine.
(ddd) Other preferred halo groups include chlorine or fluorine.
(eee) Most preferred halo groups include fluorine.
(fff) Most preferred embodiments of the present invention are: 
By virtue of their acidic moieties, some of the compounds of Formula I include the pharmaceutically acceptable base addition salts thereof. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include, but are not intended to be limited to, ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine, and the like.
Because of a basic moiety, some of the compounds of Formula I can also exist as pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include, but are not intended to be limited to, sulfate, pyrosulate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrace, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, b-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
It is recognized that various stereoisomeric forms of the compounds of Formula I may exist. The compounds may be prepared as racemates and can be conveniently used as such. Alternatively, the compounds of the present invention can be prepared as single enatiomers or diastereomers by chiral synthesis or resolution techniques well known in the art. Therefore, the racematezs, individual enantiomers, diastereomers, or mixtures thereof form part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all the racemates, individual enantiomers, diastereomers, or mixtures thereof are included in said reference or description.
The compounds of Formula I are prepared as described in the following Schemes and Examples. Schemes I and I describe methodology for the preparation of final embodiments of the present invention. Schemes III-VI represent methodology for the preparation of intermediates required for the construction of the final embodiments of the invention. 
In Scheme I, X1, X2, R1, R2, R4, R5, and R6 have the same meaning as previously described. The reaction of Scheme I is carried out under conditions known in the art for the amination of epoxides. For example, the epoxide (A) may be combined with the amine (B) in an alcohol, such as ethanol, at room temperature to the reflux temperature of the reaction mixture. Preferably, the reaction is carried under conditions generally described in Atkins et al., Tetrahedron Lett. 27:2451 (1986). These conditions include mixing the reagents in the presence of trimethylsilyl acetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide (DMF), acetone, dimethylsulfoxide (DMSO), dioxane, diethylene glycol dimethyl ether (diglyme), tetrahydrofuran (THF), or other polar aprotic solvents in which the reagents are soluble. Preferably, the solvent is DMSO. The reaction is carried out at temperatures ranging from about 0xc2x0 C. to about reflux.
Certain compounds of the present invention can be prepared by a combinatorial/parallel chemical array synthesis, as shown in Scheme II. 
In Scheme II, X1, X2, R1, R4, and R5 have the same meaning as previously described and R6 is hydrogen. The reaction of Scheme II is preferably carried out by adding to a glass vial an amine (IV), ketone (V), and a non-reactive solvent such as methanol, DMF, methylene chloride, acetonitrile, or the like. The solution is shaken at room temperature to allow for imine formation and then treated with Amberlite IRA400 borohydride resin (Aldrich Chemicals). The slurry is then shaken for about 24 hours to effect reduction to the secondary amine. Methylene chloride and polystyrene-linked benzaldehyde resin (Frechet, J. M. et al., J. Am Chem. Soc. 93:492 (1971)) is added to the vial in order to scavenge excess primary amine starting material. The slurry is shaken, preferably overnight. The slurry is then filtered and the residual solids are rinsed with methanol. Evaporation under a flow of air, followed by drying for several hours at room temperature in a vacuum oven yields the desired product of sufficient purity.
A modification of Scheme II is necessary when the amine hydrochloride salt is used. Addition of resin-bound base to the initial reaction mixture prior to reduction or scavenging allows the desired reaction to proceed. Imine formation using amine hydrochloride salts, an aldehyde or ketone, and a resin bound amine base may be carried out using one of two different resins: poly(4-vinylpyridine) commercially available from Aldrich, and resin (VIII), which can be synthesized by the reaction of Merrifield resin with piperidine as is shown in Scheme Iia. 
In Scheme IIa, PS is polysytrene. Both the poly(4-vinylpyridine) and resin (VIII) promote imine formation.
Scheme II can also be carried out by utilization of traditional techniques. For example, reductive aminations described in scheme II are well known in the art. They are typically performed by mixing the amine and ketone starting materials in a solvent and adding a reducing agent. Solvents typically include lower alcohols, DME, and the like. Although a wide variety of reducing agents can be utilized, most commonly utilized are sodium borohydride, sodium cyanoborohydride, ano the like. The reaction can be typically performed at room temperature to the reflux temperature of the solvent. Products can be isolated by techniques well known in the art.
The ketone and amino starting materials of Scheme II can be prepared by techniques which are well known by one 10 skilled in the art. The synthesis of the starting materials is generally described in Schemes III and IV. 
In Scheme III, R1is the same as previously defined. R14 is OH or SH. Equimolar amounts of the aromatic compound (Compound IX) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (Compound X) can be dissolved in an inert solvent such as acetone and treated with 1.1 equivalents of a non-reactive acid scavenger, such as K2CO3. The suspension is then heated at reflux for about 16-20 hours with stirring. The solvent can be removed in vacuo. The residue is partitioned between chloroform or other organic solvent and water. The organic layer can be dried over Na2SO4 and concentrated in vacuo to give the compound (XI) in sufficient purity ( greater than 9)5%) and yield (85-100%).
Alternatively, the compound of formula (IX) can be reacted with epichlorohydrin, by methods known in the art, to yield compounds of formula (XB). The compounds of formula (XB) can be closed to the epoxide compounds of formula (XI) by methods well known in the art.
The epoxide (XI) can be dissolved in an alcohol, preferably methanol, and treated with one equivalent of dibenzylamine. The solution is preferably stirred at reflux for about three to four hours and then cooled to ambient temperature. Approximately 10 equivalents of ammonium formate are added to the flask, followed by 10% palladium on carbon, and the suspension stirred vigorously at reflux for 30-45 minutes. The reaction mixture is cooled to room temperature and then filtered, concentrated in vacuo to a minimum volume and treated with 1.1 equivalents of a 1.0 M anhydrous solution of HCl in ether. The solution is concentrated to dryness. The solid residue is triturated with pentane to yield produces of sufficient purity and yield. If desired, further purification may be carried out by passing over a short plug of silica, eluting with CHCl3, then 95:5 CHCl3/MeOH, then 25:5:1 CHC13/MeOH/NH4OH.
Alternatively, the epoxide (XI) can be treated with a solution of methanol saturated with ammonia gas and stirred at room temperature in a sealed tube for 16 hours. This solution is then evaporated, and the residue subjected to standard purifications such as column chromatography or recrystallization. The HCl salt is then optionally produced by the addition of HCl gas Ln ether.
A skilled artisan would appreciate that, in order to increase yields or limit side products, it may be advantageous to appropriately protect the intermediates utilized in the synthesis of compounds of formula (XII). Choice of protecting groups will be governed by the ease of protection and deprotection as well as compatibility with the reaction conditions. A wide variety of protection strategies could be utilized to perform the transformations of scheme III. For examples see Greene T. W.; Protective Groups in Organic Synthesis. John Wiley and Sons, (1981).
The reaction of Scheme III is further described in U.S. Pat. No. 5,013,761 and references cited therein. U.S. Pat. No. 5,013,761 is herein incorporated by reference.
The ketone moieties of Scheme II, that are either unknown in the art or not commercially available, are prepared in accordance with Scheme IV. 
In Scheme IV, R4 and R5 are the same as previously defined. The notation ---- indicates optional branching. Preferably, R4 is a substituted phenyl. The reaction described in Scheme IV is referred to as a Heck reaction and is described in A. J. Chalk el al., J. Org. Chem. 41: 1206 (1976). The reaction is achieved by treating compound (XIII) with an arylpalladium reagent. The arylpalladium reagent is generated in situ by treating Compound (XIV) with a palladium-triarylphosphine complex. The reaction is generally carried out in under conditions appreciated in the art.
Additional amines, of the type where X2 is methylene, R4 is aryl, and R10 is aryl, heterocycle, optionally substituted aryl, or optionally substituted heterocycle, that are reacted in a manner analogous to Scheme I are prepared in accordance with Scheme V. 
R5, R6, and R10 are as previously defined and X2 is methylene. (XVII) can be prepared by reacting 4-hydroxybenzyl alcohol with excess (about 5 mol/equiv) of a compound of formula (XVIA) ty methods well known in the art (see Sh. Prikl. Kin., Vol 45, 1573-77 (1972); Russ.). The reaction can also be carried out by mixing the reagents in an aprotic solvent, preferably diglyme, and adding potassium t-butoxide (0.5 mol/equiv.). The reaction is then heated to reflux and water removed. After removal of water is complete, generally about 2-3 hours depending upon the scale of the reaction, the resulting solution is subjected to a standard aqueous work-up and the product is isolated by crystallization or other purification technique known in the art. Compound (XVII) can be reduced by methods well known in the art. Compound (XVIII) is preferably prepared by hydrogenation of the corresponding compound (XVII) over a precious metal catalyst. The hydrogenation can be affected at between about 20 and about 60 psi of hydrogen, and with a variety of solvents, temperatures, and catalysts well known in the art. The reaction is preferably carried out at about 50 psi of hydrogen over 5% palladium on carbon wetted with 2B3 ethanol. Compound (XVII) is charged to the reactor along with one equivalent of acetic acid, diluted with solvent, heated to about 50xc2x0 C., and subjected to hydrogen for about 5-24 hours depending on the scale of the reaction. The product is isolated as the acetic acid salt upon work up by methods well known in the art.
A skilled artisan would appreciate that compound (XVIII) could be coupled with a wide variety of aromatic halides to yield the ethers contemplated by the present invention. The coupling can be carried out according to procedures well known in the art and is preferably performed by mixing the starting materials in N,N-dimethylacetamide and toluene in the presence of potassium carbonate. The reaction is then heated to reflux for about 5 to about 24 hours and water removed. The product is isolated by standard techniques. The crude product can be purified by methods well know in the art. A skilled artisan would appreciate that the amines prepared by Scheme V can be utilized in Scheme I to prepare compounds of the present invention.
Additional amines capable of being utilized in Scheme I can be prepared according to Scheme IV or by methods known in the art. 
Compounds of formula XXI can be prepared by the addition of a nucleophile to the compounds of formula (XX) according to procedures well known in the art. The skilled artisan would appreciate a wide variety of conditions amenable to performing the additions. Preferred neucleophiles include, but are not intended to be limited to, alkyl grignard reagents, alkyl lithium reagents, and the like.
Compounds of formula (XXII) can be prepared from the compounds of formula (XXI) by the Ritter reaction. (See for example; Organic Reactiors, Vol. 17, pp. 213-325, (1979)).
Compounds of formula (XXIII) can be prepared by reduction of the compounds of formula (XXII) according to procedures well known in the art. Preferred reducing agents include, but are not intended to be limited to, borane complexes and the like.
Compounds of formula (XXIV) can be prepared by reduction of the compounds of formula (XXIII) according to procedures well known in the art. (See for example; Greene T. W., Protective Groups in Organic Synthesis, John Wiley and Sons, (1981)).
Starting materials for the compounds described in Schemes I, II, III, IV or V are either commercially available, known in the art, or can be prepared by methods known in the art or described herein.